{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:21:39Z","timestamp":1791886899220,"version":"4.3.4"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100003977","name":"the Israel Science Foundation","doi-asserted-by":"publisher","award":["2785\/24"],"award-info":[{"award-number":["2785\/24"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Neuropathic pain remains one of the leading causes of global disability. The mechanism of neuropathic pain development and maintenance involves mitochondrial dysfunction-induced neuronal apoptosis of peripheral and central nociceptive pathways. Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which has a high Ca2+ permeability, playing an essential role in neuronal apoptosis in the spinal cord following peripheral nerve injury. However, the mechanism of how TRPV1 activation in the spinal cord induces mitochondrial dysfunction-mediate neuronal apoptosis, resulting in allodynia is unknown.<\/jats:p>\n               <jats:p>Here, we found that activating the TRPV1 channel in the spinal cord using capsaicin, a TRPV1 agonist, results in mechanical and thermal hypersensitivity that were found to be mediated by neuroinflammation, an elevated level of apoptosis, and reduced transcription of the mitochondrial complexes in the spinal cord and dorsal root ganglion (DRG). Moreover, during the early activation of TRPV1 (1\u2005h, 24\u2005h, 48\u2005h following the capsaicin injection into the spinal cord) we observed a robust reduction in mitochondrial oxygen consumption in the non-phosphorylated state, ATP-linked respiration, maximal respiration and electron transfer capacity (ETC). A more advanced experiment, wherein we controlled capsaicin, Ca2+ concentration and exposure time in isolated spinal cord tissue (lumbar, L1\u2013L6), unveiled that TRPV1 activation impaired mitochondrial function in terms of oxygen consumption, collapsed the mitochondrial membrane potential (\u03a8m) and induction of the mitochondrial permeability transition pore (mPTP), which were reversed by the mPTP inhibitor-Cyclosporin A (CsA) during challenging the mitochondria with Ca2+ in a dose-dependent manner. More critically, injection of the TRPV1 antagonist, AMG9810, into the spinal cord following sciatic nerve crush reversed mechanical allodynia and modulated thermal hypersensitivity. In addition, the presence of the TRPV1 antagonist AMG9810 along with capsaicin and Ca2+ during challenging the spinal cord tissue completely prevents early mPTP induction, and the reduction in oxygen consumption.<\/jats:p>\n               <jats:p>In conclusion, our findings suggest that TRPV1 activation induces neuronal apoptosis, neuroinflammation and mitochondrial dysfunction in the spinal cord, reflected in mechanical and thermal allodynia. Notably, the mitochondrial dysfunction following TRPV1 activation in the spinal cord includes crucial elements that contribute to neuronal death, including mPTP induction, reduction in \u03a8m and oxygen consumption. Strikingly, regulating TRPV1 following sciatic nerve injury reverses hypersensitivity probably via protection of the mitochondria, suggesting a fundamental role for the TRPV1 pathway in mitochondrial dysfunction-mediated pain development.<\/jats:p>","DOI":"10.1093\/brain\/awaf044","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T08:35:16Z","timestamp":1738658116000},"page":"2563-2578","source":"Crossref","is-referenced-by-count":42,"title":["Novel insight into TRPV1-induced mitochondrial dysfunction in neuropathic pain"],"prefix":"10.1093","volume":"148","author":[{"given":"Yaseen","family":"Awad-Igbaria","sequence":"first","affiliation":[{"name":"Azrieli Faculty of Medicine, Bar-Ilan University , Safed 1311502 ,","place":["Israel"]},{"name":"Research Institute of Galilee Medical Center , Nahariya 2201202 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Nahariya 2201202 ,","place":["Israel"]},{"name":"Department of Neurosurgery, Galilee Medical Center , Nahariya 2201202 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2032-2974","authenticated-orcid":false,"given":"Eilam","family":"Palzur","sequence":"additional","affiliation":[{"name":"Azrieli Faculty of Medicine, Bar-Ilan University , Safed 1311502 ,","place":["Israel"]},{"name":"Research Institute of Galilee Medical Center , Nahariya 2201202 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"2025070715521680100_awaf044-B1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41392-023-01464-x","article-title":"TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for 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